Alessandro Di Minno

Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has been recognized as a major health burden. It is the most important cause of chronic liver disease and a major independent cardiovascular risk factor. Lacking a definite treatment for NAFLD, a specific diet and an increase in physical activity represent the most commonly used therapeutic approaches. In this review, major literature data about the use of omega-3 polyunsaturated fatty acids (n-3 PUFAs) as a potential treatment of NAFLD have been described. n-3 PUFAs, besides having a beneficial impact on most of the cardio-metabolic risk factors (hypertension, hyperlipidemia, endothelial dysfunction and atherosclerosis) by regulating gene transcription factors [i.e., peroxisome proliferator-activated receptor (PPAR) α, PPARγ, sterol regulatory element-binding protein-1, carbohydrate responsive element-binding protein], impacts both lipid metabolism and on insulin sensitivity. In addition to an enhancement of hepatic beta oxidation and a decrease of the endogenous lipid production, n-3 PUFAs are able to determine a significant reduction of the expression of pro-inflammatory molecules (tumor necrosis factor-α and interleukin-6) and of oxygen reactive species. Further strengthening the results of the in vitro studies, both animal models and human intervention trials, showed a beneficial effect of n-3 PUFAs on the severity of NAFLD as expressed by laboratory parameters and imaging measurements. Despite available results provided encouraging data about the efficacy of n-3 PUFAs as a treatment of NAFLD in humans, well-designed randomized controlled trials of adequate size and duration, with histological endpoints, are needed to assess the long-term safety and efficacy of PUFA, as well as other therapies, for the treatment of NAFLD and non-alcoholic steatohepatitis patients. It is worthwhile to consider that n-3 PUFAs cannot be synthesized by the human body and must be derived from exogenous sources (fish oil, flaxseeds, olive oil) which are typical foods of the Mediterranean diet, known for its beneficial effects in preventing obesity, diabetes and, in turn, cardiovascular events. According to these data, it is important to consider that most of the beneficial effects of n-3 PUFAs can also be obtained by an equilibrate nutrition program.

Obesity and psoriatic arthritis: from pathogenesis to clinical outcome and management

PsA is an axial and/or peripheral inflammatory arthritis associated with psoriasis, included in the group of spondylarthritides. It has been suggested that PsA could be a systemic disease, involving even coronary arteries and the heart. An increased prevalence of vascular risk factors has been found in PsA subjects as compared with the general population and psoriatic subjects. Moreover, PsA patients exhibit an increased prevalence of liver steatosis, a marker of metabolic syndrome, and of obesity. Interestingly, many reports demonstrate that adipose tissue is metabolically active, representing a source of inflammatory mediators, known as adipokines. The latter include TNF-α, macrophage chemoattractant protein-1, plasminogen activator inhibitor-1 (PAI-1), IL-6, leptin and adiponectin, leading to a pro-inflammatory status in obese subjects. This evidence supports the idea of obesity as a low-grade inflammatory disease. Accordingly, obesity might be associated with some rheumatic diseases. In particular, it seems to affect several features of PsA, such as its development, cardiovascular risk and clinical outcome. Recent data suggest that increased BMI in early adulthood increases the risk of PsA development in psoriatic patients, supporting a link between fat-mediated inflammation and joint involvement. Obesity may represent an additive cardio-metabolic risk factor in PsA subjects. Abdominal obesity may also determine an increased risk of not achieving minimal disease activity in PsA patients, highlighting the role of abdominal fat accumulation as a negative predictor of good clinical response to biologic agents. This review assesses the relationship between obesity and PsA according to the available literature.

Non-invasive assessment of arterial stiffness in patients with rheumatoid arthritis: A systematic review and meta-analysis of literature studies

Introduction. Patients with rheumatoid arthritis (RA) have an increased cardiovascular (CV) morbidity and mortality. Pulse-wave velocity (PWV) and augmentation index (AIx) are non-invasive methods to assess arterial stiffness, a marker of CV risk. We performed a meta-analysis evaluating the impact of RA on aortic-PWV, brachial-PWV, brachial–ankle (ba-) PWV, AIx, and AIx normalized to a 75 beats/minute heart rate (AIx@75). Materials and Methods. Studies evaluating the relationship between RA and aortic-PWV, brachial-PWV, ba-PWV, AIx, and AIx@75 were systematically searched. A total of 25 studies (1,472 RA patients, 1,583 controls) were included. Results. Compared to controls, RA patients showed a significantly higher aortic-PWV (mean difference 1.32 m/s; 95% CI 0.77, 1.88; P < 0.00001), ba-PWV (MD 198.42 cm/s; 95% CI 45.79, 342.76; P = 0.01), AIx (MD 11.50%; 95% CI 5.15, 17.86; P = 0.0004), and AIx@75 (MD 6.99%; 95% CI 4.92, 9.06; P < 0.00001), with a trend toward a higher brachial-PWV (MD 0.34 m/s; 95% CI –0.03, 0.70; P = 0.07). When analyzing studies on early RA, the difference in aortic-PWV among RA patients and controls was even higher (MD 2.30 m/s; 95% CI 1.15, 3.45; P < 0.0001). Conclusion. Meta-regression showed that a more severe inflammatory status impacted on aortic-PWV, AIx, and AIx@75. Arterial stiffness, a recognized marker of CV risk, is increased in RA patients. This alteration is associated with the severity of the inflammatory status and is present even in early-stage disease.

Old and new oral anticoagulants: Food, herbal medicines and drug interactions

The most commonly prescribed oral anticoagulants worldwide are the vitamin K antagonists (VKAs) such as warfarin. Factors affecting the pharmacokinetics of VKAs are important because deviations from their narrow therapeutic window can result in bleedings due to over-anticoagulation or thrombosis because of under-anticoagulation. In addition to pharmacodynamic interactions (e.g., augmented bleeding risk for concomitant use of NSAIDs), interactions with drugs, foods, herbs, and over-the-counter medications may affect the risk/benefit ratio of VKAs. Direct oral anticoagulants (DOACs) including Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and thrombin inhibitor (dabigatran) are poised to replace warfarin. Phase-3 studies and real-world evaluations have established that the safety profile of DOACs is superior to those of VKAs. However, some pharmacokinetic and pharmacodynamic interactions are expected. Herein we present a critical review of VKAs and DOACs with focus on their potential for interactions with drugs, foods, herbs and over-the-counter medications.

Effects of Treatment With Metformin on TSH Levels: A Meta-analysis of Literature Studies

CONTEXT Some data suggest that metformin affects the thyroid profile in patients with type 2 diabetes, but contrasting results are reported in different settings. OBJECTIVE The aim of this meta-analysis was to assess the effect of metformin treatment on TSH in subjects with or without thyroid dysfunction. DATA SOURCES We performed a systematic search of articles evaluating changes in TSH levels in patients receiving metformin. STUDY SELECTION Studies evaluating TSH levels before and after metformin treatment were included. DATA EXTRACTION Clinical data, demographic variables, and TSH levels before and after treatment with metformin were extracted. Data were analyzed according to the underlying thyroid disease. DATA SYNTHESIS A total of 7 datasets (206 patients) were included in the final analysis. After metformin treatment, a slight but significant reduction in TSH levels was found in 4 datasets on 119 patients with overt hypothyroidism receiving l-T4 replacement (mean difference, 1.08; 95% confidence interval [CI], 0.50, 1.65; P=.0003). Similarly, in 2 datasets reporting on a total of 33 patients with subclinical hypothyroidism not receiving treatment with l-T4, a significant reduction in TSH levels was reported (mean difference, 1.59; 95% CI, 1.32, 1.87; P<.00001) after treatment with metformin. In 1 dataset, including 54 euthyroid patients not receiving l-T4, no changes in TSH levels were reported after treatment with metformin (mean difference, 0.18; 95% CI, -0.20, 0.56; P=.35). CONCLUSIONS Metformin induces a reduction in TSH levels both in overt and in subclinical hypothyroidism. In contrast, no change in TSH levels is found in euthyroid patients.

Cardiovascular risk markers in patients with psoriatic arthritis: A meta-analysis of literature studies

Abstract Introduction. Several studies reported an increased cardiovascular (CV) morbidity and mortality in patients with psoriatic arthritis (PsA). We performed a meta-analysis on the impact of PsA on major markers of CV risk. Methods. Studies on the relationship between PsA and common carotid artery intima-media thickness (CCA-IMT), prevalence of carotid plaques, flow-mediated dilation (FMD), nitrate-mediated dilation (NMD), pulse wave velocity (PWV), augmentation index (AIx), and ankle-brachial index (ABI) were systematically searched in the PubMed, Web of Science, Scopus, and EMBASE databases. Results. Sixteen case-control studies (898 cases, 1,140 controls) were included. Compared to controls, PsA patients showed a higher CCA-IMT (MD 0.07 mm; 95% CI 0.04, 0.11; P < 0.0001), and a higher frequency of carotid plaques (OR 3.12; 95% CI 1.03, 9.39; P = 0.04). Moreover, a lower FMD was found in PsA subjects than in controls (MD –2.56%; 95% CI –4.17, –0.94; P = 0.002), with no differences in NMD (MD –0.40%; 95% CI –1.19, 0.39; P = 0.32). Because of the low number of studies, no meta- analytical evaluation was performed for PWV, AIx, and ABI. Despite heterogeneity among studies, PsA appears significantly associated with markers of subclinical atherosclerosis and CV risk. Discussion. These findings could help to establish more specific CV prevention strategies in this clinical setting.

Ensuring medication adherence with direct oral anticoagulant drugs Lessons from adherence with vitamin K antagonists (VKAs)

Medication adherence (taking drugs properly) is uncommon among patients on warfarin. Poor adherence to warfarin leads to an increase in adverse medical events, including stroke in atrial fibrillation (AF). Factors related to patients, physicians and the health system account for poor adherence. Direct oral anticoagulants (DOACs) are easier to use than warfarin, with fewer drug and food interactions and no need for routine blood monitoring. A proper use of DOACs may reduce the risk of stroke in AF. However, in clinical settings where no laboratory monitoring is needed, a poor medication adherence is common and may impact clinical outcomes. In the management of chronic disorders, careful knowledge of the individual patients attitudes and behaviors is a pre-requisite for a successful doctor-patient communication. To increase patients awareness of the risks and benefits of DOACs and, in turn, increase medication adherence, at each follow-up visit physicians should screen for priorities and motivational problems; check for the lack of understanding and/or knowledge; assess any health system or personal barriers to medication adherence; identify appropriate interventions and provide tailored support to patient needs. Dissemination of guidelines to the health care chain (prescribing physician, general practitioners, caregivers, nurses, pharmacists) further encourages medication adherence. However, the long-term effect of some of these strategies is unknown; one tool may not fit all patients, and the prescribing physician should consider individualization of these aids to ensure medication adherence and persistence (continuing to take drugs properly in long-term treatments) for DOACs in every day practice.

8-hydroxy-2-deoxyguanosine levels and cardiovascular disease : a systematic review and meta-analysis of the literature

Abstract Significance: 8-Hydroxy-2-deoxyguanosine (8-OHdG) is generated after the repair of ROS-mediated DNA damages and, thus, is one of the most widely recognized biomarkers of oxidative damage of DNA because guanosine is the most oxidized among the DNA nucleobases. In several pathological conditions, high urinary levels of oxidized DNA-derived metabolites have been reported (e.g., cancer, atherosclerosis, hypertension, and diabetes). Recent Advances: Even if published studies have shown that DNA damage is significantly associated with the development of atherosclerosis, the exact role of this damage in the onset and progression of this pathology is not fully understood, and the association of oxidative damage to DNA with cardiovascular disease (CVD) still needs to be more extensively investigated. We performed a meta-analysis of the literature to investigate the association among 8-OHdG levels and CVD. Critical Issues: Fourteen studies (810 CVD patients and 1106 controls) were included in the analysis. We found that CVD patients showed higher 8-OHdG levels than controls (SMD: 1.04, 95%CI: 0.61, 1.47, p < 0.001, I2 = 94%, p < 0.001). The difference was confirmed both in studies in which 8-OHdG levels were assessed in urine (MD: 4.43, 95%CI: 1.71, 7.15, p = 0.001) and in blood samples (MD: 1.42, 95%CI: 0.64, 2.21, p = 0.0004). Meta-regression models showed that age, hypertension, and male gender significantly impacted on the difference in 8-OHdG levels among CVD patients and controls. Future Directions: 8-OHdG levels are higher in patients with CVD than in controls. However, larger prospective studies are needed to test 8-OHdG as a predictor of CVD. Antioxid. Redox Signal. 24, 548–555.

Markers of cardiovascular risk in patients with antiphospholipid syndrome: A meta-analysis of literature studies

Abstract Several studies reported on the association between antiphospholipid syndrome (APS) and venous thrombosis. In contrast, little is known about cardiovascular (CV) risk in APS. We performed a meta-analysis on the impact of APS on major markers of CV risk. Studies on the relationship between APS and common carotid artery intima-media thickness (CCA-IMT), internal carotid artery IMT (ICA-IMT), carotid bifurcation IMT (BIF-IMT), prevalence of carotid plaques, flow-mediated dilation (FMD), nitrate-mediated dilation (NMD), and ankle-brachial index (ABI) were systematically searched in PubMed, Web of Science, Scopus, and EMBASE databases. Twenty case-control studies (668 cases, 678 controls) were included. Compared to controls, APS patients showed a higher CCA-IMT (mean difference [MD] 0.11 mm; 95% CI 0.07, 0.14), ICA-IMT (MD 0.08 mm; 95% CI 0.05, 0.11), BIF-IMT (MD 0.09 mm; 95% CI 0.06, 0.12) and a higher frequency of carotid plaques (OR 3.87; 95% CI 1.61, 9.31). Moreover, a lower FMD was found in APS subjects than in controls (MD –4.49%; 95% CI –6.20, –2.78), with no differences in NMD (MD –1.80%; 95% CI –4.01, 0.42). Finally, an increased prevalence of pathological ABI was found in APS patients compared to controls (OR 7.26; 95% CI 1.77, 29.71). Despite heterogeneity among studies, APS appears significantly associated with markers of subclinical atherosclerosis and CV risk. These findings can be useful to plan adequate prevention strategies and therapeutic approaches.

Clinical assessment of endothelial function in patients with rheumatoid arthritis: A meta-analysis of literature studies

BACKGROUND Several studies reported an increased cardiovascular (CV) morbidity and mortality in patients with rheumatoid arthritis (RA). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are considered non-invasive methods to assess endothelial function and surrogate markers of subclinical atherosclerosis. METHODS We performed a systematic review with meta-analysis and meta-regression of literature studies evaluating the impact of RA on FMD and NMD. Studies evaluating the relationship between RA and markers of CV risk (FMD and NMD) were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. The random-effect method was used for analyses and results were expressed as mean difference (MD). RESULTS A total of 20 studies (852 RA patients, 836 controls) were included in the final analysis. In detail, 20 studies with data on FMD (852 cases, 836 controls) and 5 studies with data on NMD (207 cases, 147 controls) were analyzed. Compared to controls, RA patients showed a significantly lower FMD (MD: -2.16%; 95% CI: -3.33, -0.98; P=0.0003), with no differences in NMD (MD: -0.41%; 95% CI: -2.89, 2.06; P=0.74). Interestingly, a lower FMD (MD: -2.00%; 95% CI: -3.20, -0.80; P=0.001) and no differences in NMD (P=0.49) were confirmed when excluding data on patients with early-RA. Meta-regression models showed that a more severe inflammatory status was associated with a more significant impairment in FMD. CONCLUSIONS RA patients show impaired FMD, which is currently considered an independent predictor of CV events. The presence of endothelial dysfunction in RA should be taken into account to plan adequate prevention strategies and therapeutic approaches.